Biologic stability, delivery logistics and administration of time and/or temperature sensitive biologic based materials

ABSTRACT

In some embodiments, alerts are sent to appropriate parties if an insulated container is not properly packed out to insure the approximate safe temperature of the materials. In other embodiments, a countdown timer is used to keep track of the time that the biologic has been in transit, and ensure that the amount of time does not exceed the known shelf life of the biologic. In still other embodiments, the payload container is equipped with its own sensors, such as temperature sensors, and communications devices, such as a close range communication device, capable of transmitting information regarding a range of parameters, including, but not limited to, temperature, humidity, location and time, from the payload container to an end user. In other embodiments, shielding and/or radiation sensors are included in insulated shipping or storage containers, or payload containers, to shield and monitor the radiation exposure of the payload.

REFERENCE TO RELATED APPLICATIONS

This application claims one or more inventions which were disclosed inProvisional Application No. 62/164,969, filed May 21, 2015, entitled“BIOLOGICAL STABILITY DELIVERY LOGISTICS AND ADMINISTRATION OF TIMEAND/OR TEMPERATURE SENSITIVE BIOLOGIC BASED MATERIALS” and ProvisionalApplication No. 62/258,805, filed Nov. 23, 2015, entitled “BIOLOGICSTABILITY, DELIVERY LOGISTICS AND ADMINISTRATION OF TIME AND/ORTEMPERATURE SENSITIVE BIOLOGIC BASED MATERIALS”. The benefit under 35USC § 119(e) of the United States provisional applications is herebyclaimed, and the aforementioned applications are hereby incorporatedherein by reference.

BACKGROUND OF THE INVENTION

Field of the Invention

The invention pertains to the field of transport and storage ofbiologic-based medicines and other biologics. More particularly, theinvention pertains to biologic stability, delivery logistics andadministration of time and/or temperatures sensitive medicines and otherbiologic based materials.

Description of Related Art

Most all biologic-based materials including medicines, vaccines, celland gene therapies and engineered tissue products are subject tohypothermic storage of varying duration to attempt to ensure survival,recovery during an ex vivo storage interval, and return to normalbiologic function following an ex vivo storage interval. All vaccinesand 70% of biologics are temperature sensitive. Regenerative medicinetherapies require precise thermal protection during shipment. Currentmethods deploy various insulated shipping containers, biopreservationmedia of varying formulas, and data loggers that record the containertemperature and store this on fixed media.

Temperature sensitive biologic-based medicines and other biologics thatare subjected to temperature excursions may suffer degradation so as torender them ineffective.

One of the common causes of temperature excursions in temperaturesensitive packaging and shipping is due to failure of the pack outpersonnel to follow the prescribed procedures for packing out ashipment, resulting in pack out errors. In addition, traditionalshipping containers have limited temperature stability.

The consequences of these errors can be extremely costly, when abiologic based medicine cannot be administered due to temperatureexcursions outside a validated temperature range, or if the shipment isdelayed and the medicine cannot be administered once the dosage hasexceeded its validated stability period. Cell viability declines or lostand unusable doses of the medicines are also possible. Administering athermally sensitive biologic dose that was exposed to unknowntemperature excursions, pack out errors or has exceeded it stabilityperiod is dangerous. Clinical impacts can potentially include the lossof life of a patient, who may be dependent on a biological, ortemperature sensitive material achieving its desired therapeutic effect.Additional clinical impacts include negative impacts on clinical trialoutcomes due to poor biologics management. There is also potentially alarge economic burden from waste and scrapping of unusable biologicalmaterials due to errors in shipping.

An additional challenge for the successful shipment of a temperaturesensitive material is the monitoring of the temperature and a range ofother important parameters, which, if they vary outside of acceptedand/or validated ranges, may harm the material being transported.

A further risk relating to the safe and proper handling of the shipmentof these materials relates to the time window for use of the materials.Many biological materials may only be used for treatment within aspecific time window, or stability period.

Prior art foam shipping containers such as extruded or expandedpolystyrene have limited performance, can only be used a single time,and have a negative environmental impact. In addition, it is difficultto control the temperature in these containers.

Prior art vacuum panel shippers have a very large footprint, and areheavy. They also have a complicated assembly or pack out procedure andare expensive to ship. The insulating materials used in these shippersmust be preconditioned to multiple temperature ranges prior to use.

U.S. Pat. No. 8,154,421, issued Apr. 10, 2012, entitled “REAL TIMETEMPERATURE AND LOCATION TRACKER”, herein incorporated by reference,discloses a shipper having an outer housing with a temperature sensitivepayload and a temperature/location tracker. The payload andtemperature/location tracker are within a compartment of a body of theshipper. The temperature/location tracker has a first temperature probe,a GPS receiver, a cellular modem, and a GPS antenna. The trackermonitors and periodically transmits temperature and location values ofthe shipper over a cellular communication network.

Various causative agents, including radiation exposure, may also impactthe viability and functionality of biologics. Biologics that areutilized for research and clinical applications (regenerative medicine,drug discovery, and biobanking) include, but are not limited to, cellsor cell types that are generally shielded from natural andmedical/industrial radiation by tissues, fat, bones, organs, etc. intheir normal conditions. When packaged for therapeutic doses, theseisolated cells and tissues are more vulnerable to radiation, and theimpact of radiation exposure may result in lethal and sub-lethalcellular responses.

Lethal radiation, at the minimum of assessment parameters, results infailure of the biologic for its intended use. The loss of biologicintegrity results in the biologic product not being utilized in theresearch or clinical application. The immediate consequences of lethalradiation would include loss of product for the patient or customer,loss of time in the clinical/research workflow, and/or loss ofcost-of-goods and revenue. Generally, the recognition of altered productdue to lethal radiation exposure would result in scrapped product andnon-usage. Perhaps even more problematic would be the lack ofrecognition of negative impact to the biologic, which may result inusage within the research/clinical application. Negative consequences ofuse of the impacted biologic include patient reactions and alteredresearch results.

Sub-lethal radiation can also cause alterations and altered activity inbiologics. One risk with exposure to sub-lethal radiation is thatbiologic alterations may not be recognized via superficial assessmentmethods, and may be delayed in manifesting their alterations outside ofroutine assessment timing parameters. Furthermore, the biologicalterations from sub-lethal radiation may result in altered biologicresponses that can vary from mild to extensive consequences. Protectionfrom radiation that may result in sub-lethal exposure would also bebeneficial for maintaining the integrity and quality of biologics.

Within regenerative medicine, drug discovery, and biobanking, cells andtissues may be of particular concern regarding radiation exposure, astheir utility is related to maintenance of yield, viability, andfunctionality. Furthermore, lethal and sub-lethal radiation exposure canelicit cellular responses resulting in negative consequences beyondsimple inactivation of the cell/tissue product. In addition, cells andtissues may be subjected to biopreservation steps (hypothermicpreservation, cryopreservation) with inherent sensitivities that caninstill cumulative stresses and sensitivities in combination withradiation exposure.

The effects of radiation in mammalian cells include, but are not limitedto, gene mutation, chromosomal rearrangement, cellular transformation,cell death via apoptosis, necrosis, and secondary necrosis, andcarcinogenesis. Deleterious effects of ionizing radiation (IR),including mutation and carcinogenesis, are due to cellular level damage,often at the point of the nuclear DNA via direct absorption of radiationenergy, with surviving irradiated cells expressing alterations, and celldeath of other cells resulting from direct cellular damage.

Radiation damage to the cell can be caused by the direct or indirectaction of radiation on the DNA molecules. In direct action, theradiation disrupts the molecular structure of the DNA by targeting theDNA molecules directly. These disruptions lead to cell damage or celldeath. Surviving damaged cells may later induce abnormalities orcarcinogenesis. In indirect action, water molecules and other organicmolecules in the cell (where free radicals such as hydroxyl and alkoxyare produced) are targets of the radiation. Since water makes up nearly70% of the cell composition, most radiation induced damage results fromindirect action. Direct and indirect effects cause biological andphysiological alterations that may surface immediately or only after aprolonged period of time, such as decades or even longer. Specificcellular responses seen in response to low dose or low dose rateradiation include the radioadaptive response, the radiation-inducedbystander response, low dose hyper-radiosensitivity, and genomicinstability. (Desouky et al., “Targeted and Non-Targeted Effects ofIonizing Radiation”, Journal of Radiation Research and Applied Sciences,2015, pp. 247-254, herein incorporated by reference)

The deleterious effects of radiation can also occur in the progeny ofirradiated cells after a delay. These deleterious effects are generallycategorized as radiation-induced genomic instability (RIGI). Genomicinstability is considered one of the most important aspects of cancer.(Huang et al., “Radiation-induced genomic instability and itsimplications for radiation”, Oncogene (2003) 22, 5848-5854, hereinincorporated by reference).

Humans and other organisms respond differently to low dose/low dose-rateradiation than they do to high dose/high dose-rate radiation. Non(DNA)-targeted effects include radiation-induced bystander effects(RIBE), genomic instability (GI), adaptive response, low dosehyperradiosensitivity (HRS), delayed reproductive death and induction ofgenes by radiation. “Non-targeted” effects do not require that nuclearDNA is directly exposed to irradiation to be expressed and they areparticularly significant at low doses. Radiation-induced bystandereffects (RIBE) are occurrences of biological effects in non-irradiatedcells as a result of exposure of other cells in the population toradiation. Bystander effects have been mainly observed in high densitycell cultures where only a small fraction of cells is irradiated. RIBEhave been observed in DNA damage induction, the induction of mutations,micronuclei (MN) formation, sister chromatid exchanges (SCE),chromosomal instability (CIN), transformation, cell death (secondarynecrosis or apoptosis), altered gene expression, differentiation, andalteration in the microRNAs (miRNAs) profile. One mechanisms of RIBE isgap-junction mediated intercellular communication (GJIC) which dependson the intercellular gap junctions' ability to transmit signals fromirradiated to non-irradiated cells. (Desouky, 2015).

Radiation induced Genomic Instability (RIGI), observed in the progeny ofirradiated cells, is a delayed appearance of de novo chromosomalaberrations, gene mutations and reproductive cell death. There issignificant overlap between RIGI and the GI (genomic instability)observed in some (non-radiation-induced) cancers. Bone marrow cellsirradiated with a low dose of ionizing high-LET alphaparticles (with amean of one particle per traversed cell) resulted in significantexpression of Chromosomal Instability (CIN) in vitro and in vivo. RIBE,observed in non-irradiated cells, may occur as a result of cellsreceiving signals from irradiated cells through gap junctioncommunications or media from irradiated cells via diffusible factors.RIBE has been observed in a range of cell types, following a variety ofradiation types and exposure procedures, particularly at low doseexposure. (Kadhim et al., “Non-targeted effects of ionizingradiation—implications for low dose risk”, Mutat Res. 2013; 752(1):84-98, herein incorporated by reference).

Irradiated cells may induce bystander mutagenic response in neighboringcells not directly exposed to radiation. (Zhou et al., Induction of abystander mutagenic effect of alpha particles in mammalian cells”, PNAS,2000, vol. 97 no. 5, pp. 2099-2104, herein incorporated by reference).It is also noteworthy that bystander effects mediated via thesurrounding media and gap junctions may also be mediated via thebiopreservation media that is utilized for non-frozen preservation andcryopreservation of the cells and tissues. It is also possible that thecomposition of the biopreservation media may modulate the extent ofradiation-induced cell damage. Intracellular-like biopreservation mediahas been shown to modulate biopreservation-induced cell damage and celldeath (U.S. Pat. No. 6,045,990, herein incorporated by reference.Additionally, intracellular-like media has higher viscosity andgenerally contains high molecular weight components, in comparison toisotonic media, that may impede extracellular radiation-inducedsignaling factors that may result in bystander effects via mediatransfer and gap junction interactions.

Most cells being shipped or stored are subjected to hypothermicpreservation or cryopreservation. Shipped cells may likely be exposed tosome level of radiation during transport conditions and protocols. Asdiscussed above, exposure to radiation during shipping/transport may bedeleterious to cells. Furthermore, hypothermia and cryopreservation havethe potential to have deleterious effects in isolation of radiation, andthat might be noteworthy in combination with radiation exposure.Radiation-based DNA damage is potentially cumulative to, oramplification of, existing DNA damage from biopreservation of cells.

Hypothermia has been shown to enhance the radiation sensitivity of somecell types (Xiang et al., “Effects of anesthesia-induced modesthypothermia on cellular radiation sensitivity”, Science in China (SeriesC), Vol. 45, No. 1, 2002, herein incorporated by reference).Cryopreservation significantly increased (up to 140%) DNA damage incells compared with that observed in fresh samples. A source ofantioxidants may also provide reduction in DNA damage. (Del Bo et al.,“Comparison of DNA damage by the comet assay in fresh versuscryopreserved peripheral blood mononuclear cells obtained followingdietary intervention”, Mutagenesis, 2015, 30, 29-35, herein incorporatedby reference).

Telomere shortening is related to cell aging, senescence, and onset ofcell death. Cryopreservation generates single-strand breaks in telomericDNA. An increase of single-strand DNA breaks in terminal restrictionfragment (TRF) were found in cryopreserved cells after thawing. The rateof mean TRF length shortening was accelerated after cryopreservation.(Honda et al., “Induction of Telomere Shortening and ReplicativeSenescence by Cryopreservation”, Biochemical and Biophysical ResearchCommunications 282, 493-498, 2001, herein incorporated by reference).

Bystander effects cause damage in non-irradiated cells, whichexaggerates the effect of low doses. There is also evidence of anadaptive response, where some cells exposed to low dose radiation havereduced sensitivity to subsequent stresses. (Zhou et al., “Interactionbetween Radiation-Induced Adaptive Response and Bystander Mutagenesis inMammalian Cells”, Radiat Res. 2003, 160(5): 512-516, herein incorporatedby reference). This may cause cells intended to have transienttherapeutic lifespans to remain in the body longer than intended, withcontinued activity, and/or be resistant to suicide switches to preventprogression into cancer cells or intended to inactivate cells causingGraft vs. Host Disease (GHVD) or cytokine overload. Although much focusis on the potential for radiation-induced effects resulting in celldamage or cell death, there is also concern for radiation-inducedcellular changes that may result in pro-survival activity andproliferation beyond normal cell control mechanisms. Development ofcell-based therapies takes into consideration the potential for cellularchanges that result in cell degradation, but they also take intoconsideration the potential for uncontrolled cellular activity that mayalso lead to overall negative consequences for research and clinicalapplications.

SUMMARY OF THE INVENTION

In some embodiments, alerts are sent to appropriate parties if aninsulated container is not properly packed out to insure the approximatesafe temperature of the materials. In other embodiments, the payloadcontainer is equipped with its own sensors, such as temperature sensors,and communications devices, such as a close range communication device,capable of transmitting information regarding a range of parameters,including, but not limited to, temperature, humidity, location and time,from the payload container to an end user.

An insulated shipping container includes an insulated shipping containerbody comprising a base and sidewalls extending from the bottom of thebase and a removable top which fits onto the body. The shippingcontainer also includes a plurality of sensors and/or switches at leastpartially embedded into the sidewalls of the insulated shipping body.The plurality of sensors and/or switches are located in the body suchthat the sensors and/or switches sense a location of insulation materialand a payload container placed into the insulated shipping containerprior to shipping. The shipping container also includes a long-rangecommunications device located within a cavity of the insulated shippingcontainer body, to transmit information from the sensors and/or switchesto a communications network. The sensors and/or switches are operativelyconnected to the long-range communications device.

A method of determining whether an insulated shipping containercontaining a temperature sensitive biologic has been packed correctlyincludes the steps of a computer receiving sensor information from aplurality of sensors and/or switches and determining whether componentsin the insulated shipping container have been packed correctly based onthe sensor information.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows an example of an empty insulated shipping container in anembodiment of the present invention.

FIG. 1B shows the insulated shipping container of FIG. 1A, packed withinsulating materials and the payload container and examples of locationsfor the switches and/or sensors in the shipping container.

FIG. 1C shows an embodiment of an insulated shipping container, usingmagnetic switches.

FIG. 2A shows a list of pending shipments, as well as the stability timeremaining for shipments that have been recently delivered.

FIG. 2B shows parameters being monitored and when alarms may be sent ifthose parameters are outside certain ranges. The numeric ranges andvalues displayed are for illustrative purposes only. The actual valuesdepend upon many factors, including, but not limited to, the biologicbeing shipped and the distance and time of transport.

FIG. 2C shows an example of the pack out time and stability period beingreceived into the system, as well as possible alert options.

FIG. 2D shows information on pending shipments, recently deliveredbiologic shipments (with stability time remaining) and other parameters.

FIG. 2E shows an example of a shipment report.

FIG. 3A shows an example of a payload container in an embodiment of thepresent invention.

FIG. 3B shows a cross-sectional view of a payload container in anotherembodiment of the present invention.

FIG. 4A shows an insulated shipping container with a communicationsdevice plus shielding in an embodiment of the present invention.

FIG. 4B shows the insulated shipping container of FIG. 4A, packed withinsulating materials and the payload container.

FIG. 4C shows the insulated shipping container of FIG. 4A, packed withinsulating materials and a payload container, which is also shielded.

FIG. 5 shows an insulated shipping container with a communicationsdevice plus at least one sensor to detect non-ionizing radiationexposure in an embodiment of the present invention. The insulatedshipping container is packed with insulating materials and the payloadcontainer. The insulated shipping container could also contain shielding(as shown in FIGS. 4A to 4C) to shield the payload container from thecommunications device.

FIG. 6 shows an insulated shipping container with a communicationsdevice plus at least one sensor to detect ionizing radiation exposure inan embodiment of the present invention. Although a communications deviceis shown in this figure, simple shipping or storage containers withoutthese devices could also utilize the radiation sensors shown in thisfigure. In the figure, the insulated shipping container is packed withinsulating materials and the payload container.

FIG. 7 shows a payload container with shielding and radiation sensors.

FIG. 8 shows a shipping container in an embodiment of the presentinvention, with the shielding shown in FIG. 4 and the switches and/orsensors shown in FIG. 1.

DETAILED DESCRIPTION OF THE INVENTION

Due to the critical nature of the temperature sensitive biologics, andthe fact that a critical treatment may be awaiting the receipt of thisshipment, it is extremely important that the status of the conditions ofthe shipment and its location are being reported in real time or nearreal time for review by the parties involved. There is a need in the artfor real-time temperature monitoring and reporting during shipment.

There is also a need for a countdown timer to be available for all theinterested parties to ensure that the biologic material is scheduled foruse and used for treatment within a validated stability period.

There is also a need in the art to protect biologics from radiationexposure (both lethal and sub-lethal amounts), as well as sensing theextent of exposure of those biologics during storage and shipping. Themethods and devices herein preferably protect the biologics fromradiation that may result in non-lethal and/or lethal exposure, thusmaintaining the integrity and quality of the biologics.

DNA damage mechanisms from both biopreservation and shipping radiationmay be cumulative. Protective capabilities in both the biopreservationmedia and the shipping container would provide multiple mechanisms ofprotection. Therefore, improved shipping protection from radiationduring shipping would reduce the risk of direct and indirectradiation-induced cell damage.

The methods and devices described herein provide people with bettertools to manage the logistics of time sensitive materials and improvepatient care.

“System”, “tracking system”, “logistics system”, and “tracking/logisticssystem” are used interchangeably herein to indicate the logistics systemthat improves delivery logistics of the biologic being transported.

The present disclosure describes methods and devices to improve deliverylogistics of time and/or temperature sensitive biologics. The containersdescribed herein are thermally insulated containers intended fortemporary storage of temperature-sensitive contents, such as biologicalor pharmaceutical products, during transport to a remote location. Thecontainers are equipped with integrated electronics capable ofmeasuring, storing, monitoring, tracking and communicating importantinformation regarding the location of the container and the environmentinside the container, where the temperature-sensitive contents arestored.

The containers are part of a logistics system and method of real-timemonitoring of the location, internal temperature, and other parametersof the container or the biologics within the container. The integratedelectronics are capable of broadcasting information regarding thecontainer through the use of a global positioning system (GPS) and/orother wireless technologies, such as local area wireless communication(Wi-Fi), Bluetooth, cellular network, or other wireless networks.

In preferred embodiments, information regarding the container iswirelessly exchanged with cloud-based data storage or othercommunication networks. The container provides real-time and/orhistorical location and temperature data, as well as levels of radiationexposure, which can be processed and provided to customers or otherusers on multiple platforms in various formats. For example, theinformation from the container may be provided to users via mobiledevices through short message service (SMS) and/or multimedia messagingservice (MMS). In other embodiments, the information may be accessiblevia a cloud based database or from generated reports.

Embodiments of the present invention may be implemented in a cloudcomputing environment or with any other type of known or futuredeveloped computing environment.

A computer system/server may be utilized in distributed cloud computingenvironments where tasks are performed by remote processing deviceslinked through a communications network. In a distributed cloudcomputing environment, program modules may be located in both local andremote computer system storage media including memory storage devices. Acomputer system/server computer may also communicate with one or moreexternal devices, such as device computers. The computer system/servercomputer typically includes a variety of computer system readable media.This media may be any available media that is accessible by computersystem/server computer, and includes both volatile and non-volatilemedia, as well as removable and non-removable media.

Cloud computing enables convenient, on-demand network access to a sharedpool of configurable computing resources (e.g. networks, networkbandwidth, servers, processing, memory, storage, applications, virtualmachines, and services) that can be rapidly provisioned and releasedwith minimal management effort or interaction with a provider of theservice.

The container may also communicate information regarding the containeritself (e.g. temperature information, location information, informationregarding levels of radiation exposure) to a local user or networkduring non-transit periods.

In some embodiments, alerts are sent to appropriate parties if aninsulated container is not properly packed out to insure the approximatesafe temperature of the materials. In other embodiments, a countdowntimer is used to keep track of the time that the biologic has been intransit, and ensure that the amount of time does not exceed the knownshelf life of the biologic.

In still other embodiments, the payload container is equipped with itsown sensors, such as temperature sensors or dosimeters to sense levelsof radiation exposure, and with close range communication devices,capable of transmitting information regarding a range of parameters,including, but not limited to, temperature, humidity, location, levelsof radiation exposure, and time, from the payload container to an enduser via a mobile device application, the cloud hosted application, oranother receiving system. Some close range communications devices thatcould be used include, but are not limited to, active RFID devices, RFIDtags, RF transmitters, iBeacon™ transmitters, ZigBee® transmitters,Bluetooth transmitters, Wi-Fi radios, or other wireless transmitters.

The biologic based materials being transported may be any biologicalmaterial, including, but not limited to, specimens, vaccines, medicines,pharmaceuticals, blood samples, cells, stem cells, tissues, engineeredtissue products, manufactured cell and gene therapies, organs, or anyfluid, bone or cellular or metabolic byproduct, intermediary, orderivative.

The insulated shipping container preferably includes sensors and/orswitches to determine if an insulated container was packed out properly.The switches or sensors may include, but are not limited to, mechanicalswitches, magnetic switches, LED emitting detector pairs or otheroptical switches/sensors that project a beam of light at a particularwavelength, temperature sensors, pressure sensors, and/or other sensorsincluding communication sensors that communicate with the insulatedmaterials and payload container via any form of radio frequency (RF)communication.

The insulated materials, for example gel packs or cold packs, need to beplaced in the insulated shipping container correctly in order to providethe correct temperature and temperature stability required for shipment.Similarly, the payload container (the container housing the biologicbeing transported) needs to be placed correctly. The payload containercould be of any shape that can safely ship the biologic. The payloadcontainer could be a larger container preferably containing packingmaterial to protect the payload from mechanical vibration, shock, orother forms of stress during transit. The larger payload containercontains a smaller container, such as a vial, a specimen tube, a bag, ora syringe, that is in the larger container. In other embodiments, thepayload container could be the container that actually houses thebiologic.

The mechanical, magnetic or optical switches or sensors detect thepresence or the absence of the required internal components of theshipping container. This is accomplished either physically (using themechanical switches), magnetically (using reed switches/actuators in themagnetic switches), or optically (using light radiation of a certainwavelength). The temperature sensors, if present, also come into contactwith the internal components to measure the temperature of thosecomponents.

The purpose of the switches/sensors is to prevent a biologic that wasnot packed correctly from being packed out and shipped. If the switchesor sensors are not activated properly then the insulated container willutilize the embedded communications equipment to alert the appropriateparties prior to actual shipment of the container.

Optical sensors detect the presence or absence of the insulatingmaterials (for example gel packs or ice packs) and the payload containerwhen a light beam is broken. For mechanical switches, the actuator isphysically moved by direct contact with the materials being packed. Reedswitches or other actuators in magnetic switches are moved by a magneticfield. Temperature sensors verify that insulating materials have beenpreconditioned appropriately. For examples, gel packs change phase fromliquid to solid at known temperatures and the suppliers or manufacturersinstruct users to pre-condition these in a freezer or refrigerator for aminimum time duration. A temperature sensor in near proximity to a gelpack measures the temperature on the outside of the gel pack. If the gelpack is not at least at some minimum temperature, the sensorcommunicates that information to the computer, indicating that the gelpack is not ready. The computer can then alert the user of this problem,and/or block the shipment of the biologic until the proper temperaturehas been reached. The alert may include information that the particulargel pack should not be used. It also may include information that thereis no confidence that the payload temperature will be maintained withina validated range and profile throughout the stability period.

In some embodiments, the insulated shipping container and/or the payloadcontainer include one or more temperature sensors. In embodiments wheretemperature sensors are used, they may come into contact with, be indirect contact with, or be in close proximity to whatever they aremeasuring in order to sense the temperature of that item or itsenvironment. If the insulated materials being used in the packing werenot conditioned or frozen sufficiently, these sensors alert a userregarding the improper preconditioning of the insulating materials,halting further packaging and shipping of the biologic until theseerrors are corrected.

The sensors are preferably at least partially embedded or fully embeddedinto one or more of the walls of an insulated shipping container. Thesensors and switches indicate the proper placement of liquid, gel, orother insulating packs or materials and payload boxes or containerswithin the insulated shipping container. These sensors communicateeither via hard wires or near field communication methods to along-range communications device which itself is embedded into the bodyof the insulated shipping container. The long-range communicationsdevice may utilize cellular communication or other communicationnetworks to communicate with a user. In some embodiments, a cellularmodem is integrated into the communications device.

In some embodiments, sensors may also be embedded in the insulatingmaterials, such as gel packs. In these embodiments, the sensors provideinformation to the logistics system regarding the presence, absence, andcondition (e.g.—temperature) of the gel packs. In some embodiments, thesensor in the insulating material is an RFID tag, a temperature sensor,or a magnet.

The logistics/tracking system may contain the ability to completeshipping air bills, and communicate with appropriate users as to thestatus and location of a particular shipping container. Thelogistics/tracking system may also prevent the completion of an air billif the pack out procedures are not properly followed, resulting inactivation of the built in sensors and/or switches. Thelogistics/tracking system may be cloud-based, a client application,and/or a mobile application.

There are potential deleterious effect of radiated radio frequency andother energy sources on mammalian cells, tissues, organs, and species.In some embodiments, methods and devices described herein protectbiologic payloads (for example, cells and tissues) from these energysources, some of which are used to monitor payload status as describedherein.

In preferred embodiments described herein, the communications device inthe shipping or storage container is a long-range communications devicesuch as a cellular device for cloud or other communication and alsopreferably uses near field electronic communication to provideinformation and may communicate using iBeacon™, Zigbee®, Bluetooth®,Wi-Fi or other forms of near field communication (NFC). In these methodsand devices, the communication devices may transmit information to otherdevices utilizing near field communication methods. Some examples ofthese communications devices include, but are not limited to, cellularcommunication devices (e.g.—cellular phones, cellular modems, codedivision multiple access systems, global system for mobilecommunications, and other cellular portions of the spectrum), RFtransmitters, active RFID devices, RFID tags, iBeacon™ transmitters,ZigBee® transmitters, Bluetooth® transmitters, Wi-Fi radios, otherwireless transmitters, or other near field communication signals ordevices.

In some embodiments with a communications device in the payloadcontainer, the communications device in the payload container is a nearfield communication device that provides information and maycommunicate, for example with the shipping or storage container or asmartphone device, using low power communications including Bluetooth®,iBeacon™, ZigBee®, Wi-Fi or other forms of near field communication(NFC).

In some embodiments, insulation or attenuation shielding materials areadded to shipping or storage containers to limit exposure of biologicpayloads in various shipping or storage containers to radiated energy(ionizing radiation or non-ionizing radiation) from embedded or nearbycommunications devices. In some embodiments, the materials attenuateionizing radiation (e.g.—X-ray radiation such as airport screeningdevices).

In some embodiments, methods and devices herein use sensors,communication devices, and software to measure and report non-inoizingradiated energy exposure of the biologic payload inside a shipping orstorage (non transported) container.

In other embodiments, methods and devices herein use sensors,communication devices and software to measure and report any ionizingradiation, such as X-ray energy, that gets to the biologic payloadinside a shipping or storage (non-transported) container.

In some embodiments, the biologic payload in a shipping or storagecontainer is shielded from the non-ionizing radiated energy of thecommunications device. The shielding may be made of any material thateffectively blocks radiation from the communications device including,but not limited to, lead, aluminum, bronze, copper, nickel, zinc,another metal, conductive plastics, or carbon based materials.

One way to shield the payload container is to use a plate in theelectronics cavity that still permits the communications device, totransmit. In some embodiments, the plates are made from lead, aluminum,bronze, copper, nickel, zinc, another metal, conductive plastics, orcarbon based materials. The plate is preferably placed in theelectronics cavity, or in another location between the communicationsdevice and the payload container. Another way to shield the payloadcontainer uses a coating, for example a sprayed shielding such as acoating applied with an electric arc spray gun. In some preferredembodiments, the coating is an electric arc sprayed zinc coating. Thecoating could be applied to an interior of a liner between thecommunications device and the payload container. In one preferredembodiment, a metallic coating is sprayed on the underside of a linerusing an electric arc spray gun. The coating could alternatively beapplied directly to the interior or exterior surface of the shippingcontainer. Alternatively or additionally, the coating could be appliedto the interior and/or exterior surface of the payload container itself.In some embodiments, the coating may be made from lead, aluminum,bronze, copper, nickel, zinc, another metal, conductive plastics, orcarbon based materials. The coatings chosen are preferably made ofmaterials that allow X-rays to pass through so that all interior spacesof the shipping container are still visible.

In other embodiments, the shielding may be inserts, sprayed on liners,mesh, foil, foam, paints, inks, solid plates or pieces, or a filmadhesive. In these embodiments, the shielding is made from lead,aluminum, bronze, copper, nickel, zinc, another metal, conductiveplastics, or carbon based materials.

In some embodiments, methods and devices use sensors, communicationdevices and software to measure and report any exposure of the biologicpayload inside a shipping or storage (nontransported) container tonon-ionizing radiation (such as radio frequency energy from cellularmodems or other communication devices). In some embodiments withshielding, a sensor is included within the payload container. The sensorcould be inside the payload container, or integrated within the body ofthe payload container. For example, a radiation detector of variousembodiments. One such radiation detector is a modular device with awired sensor incorporating a radiation detector diode (such as theSPD9441 Radiation Detector PIN Diode, Solid State Devices, Inc., LaMirada, Calif.,http://www.ssdi-power.com/Resources/Documents/[300]SPD9441_DS.pdf,herein incorporated by reference). The shipping containers and payloadcontainers may be tested prior to use to assess how much electromagneticradiation gets into the containers and what levels prevent cloudcommunication. As another example, a spectrum analyzer with an antennain the payload cavity could collect all of the radiation data. Thiscould also indicate whether signal strength from the communicationsdevice is sufficient to properly transmit data from the shippingcontainer to the cloud and other external receivers. Another example isa USB spectrum analyzer for detecting and measuring emittedelectromagnetic radiation from cell phones or other sources (such as theTSA6G1 USB Mini Spectrum Analyzer, Triarchy Technologies Corp., Surrey,British Columbia,http://www.triarchytech.com/Downloads/TSA6G/Datasheet_TSA6G1_11.pdf,herein incorporated by reference).

In some embodiments, methods and devices use sensors, communicationdevices and software to measure and report any ionizing radiation,including X-ray energy, that gets to the biologic payload inside ashipping or storage container (non-transported). Sensors to detectradiation levels may be used to detect levels of X-ray exposure (with orwithout shielding). Some examples are small form factor ionizationdetector chips and sensors that could be embedded in a shippingcontainer. Another example is a modular device with a wired sensorincorporating a radiation detector diode (such as the SPD9441 RadiationDetector PIN Diode, Solid State Devices, Inc., La Mirada, Calif.). Thiswould capture data on payload exposure to X-rays. This data would beuseful in determining the level of exposure of the biological payloadduring transport. Real time or near real time monitoring of X-ray energyon mammalian cells also enables longitudinal studies on impact of cellviability and function following exposure Improved shielding methodsprotect the biologic payload from deleterious energy sources. The X-raysensor may be wired or wireless and communicates with the communicationsdevice (e.g.—near field transmitter or cell modem) to get the dataexternally transmitted (e.g.—to the cloud).

An example of an insulated shipping container 1 with sensors/switches 2,4, 6 is shown in FIGS. 1A and 1B. The insulated shipping container 1 mayalso optionally contain one or more temperature sensors 11 such asthermocouples. While there is only one temperature sensor 11 shown inFIG. 1B, multiple temperature sensors 11 may be present in differentlocations throughout the insulated shipping container 1. Depending upontheir locations, the temperature sensors could monitor the temperatureof any of the materials (top or bottom insulating material or payloadcontainer) in the insulated shipping container. The temperature sensors11 are preferably connected to the communications device 3 via hardwiring. In alternative embodiments, the temperature sensors 11 arewirelessly connected to the communications device 3.

The insulated shipping container 1 includes a bottom or body 20 and atop or lid 15. The body 20 includes a base 23 and sidewalls 13 thatextend up from the base 23. The body 20 defines an open storage volumeor cavity 12. The top 15 is removable to provide access to the storagevolume 12. When the top 15 is placed on the body 20, the storage volume12 is closed. The top 15, the base 23 and the sidewalls 13 preferablyinclude multiple layers of insulating materials.

In some preferred embodiments, the layers of insulating materialsforming the body 20 and top 15 of the insulated shipping containerinclude an aerogel layer and a foam layer sandwiched between and incontact with inner and outer plastic layers. In some examples, theplastic layers are preferably ABS (Acrylonitrile Butadiene Styrene)plastic layers. The outer and/or inner plastic layers may alsopreferably be covered with an EVA (ethylene vinyl acetate) materiallayer. Other insulating materials for the body and top of the insulatedshipping container, as known in the art, may alternatively be used.

The payload container 8 is placed between the insulated materials 5 and7 in the inner cavity 12 of the insulated shipping container 1. Thesensors 2, 4, 6 are preferably embedded into one or more of thesidewalls 13 of the insulated shipping container 1. The sensors may bepartially or fully embedded into the sidewalls 13. The switches orsensors 2, 4, 6 are preferably located in the shipping container 1 atlocations where they can sense the location and placement of theinsulation materials 5 and 7, and the payload container 8, which housesthe biologic. In preferred embodiments, the payload container 8 alsoincludes a communications device 9 and/or a temperature sensor 10 (shownin FIG. 3B).

FIGS. 1A and 1B show an example of a configuration of the sensors andswitches where the switches or sensors 2 sense the insulation material5, switches or sensors 4 sense the payload container 8, and switches orsensors 6 sense the insulation material 7. Additional switches orsensors 2, 4, 6, may be included to increase the sensing accuracyregarding conditions of the biologic.

At least one communications device 3 is preferably placed in theshipping container 1. The communications device 3 is preferably housedin a cavity 26 in the base 23 of the insulated shipping container 1. Insome embodiments, the communications device 3 includes GPS, a cellularmodem, and/or other wireless communication devices. The wirelesscommunication devices are preferably permanently integrated into thebase 23 of the container 1.

The insulated shipping container 1 also preferably includes a powercompartment 45, which provides power to the electronics in the insulatedshipping container 1. In some preferred embodiments, the powercompartment 45 is a battery compartment 45, which contains a batterypack. The battery pack preferably powers the communications device 3.While the power compartment 45 is shown on the bottom of the insulatedshipping container 1 in the Figures, the power compartment 45 may be inalternative locations, and is preferably connected (via wiring) to thecommunications device 3.

The sensors/switches 2, 4, 6 are preferably connected to thecommunications device 3 so that the information from thesensors/switches 2, 4, 6 is transmitted to the communications device 3.In some embodiments, as shown in FIGS. 1A and 1B, the sensors/switchesare connected to the communications device 3 using wiring 41. In otherembodiments, the sensors and/or switches are wirelessly connected to thecommunications device 3.

The communications device 3 permits the insulated shipping container tocommunicate to an outside source, including, but not limited to, acloud-based database or program, device computers, server computers, orother devices. It should be noted that the term “outside” means with adevice other than present within the shipping container. While thecommunications device 3 is shown placed in the base 23 of the shippingcontainer 1 in FIGS. 1A and 1B, the communications device may be in anylocation where it does not interfere with the switches/sensors.

This communication device 3 communicates to an outside source including,but not limited to, a cloud-based database or program, device computers,server computers, or other devices. The outside source can alsodetermine whether certain parameters are not within appropriate rangesand notify users. The tracking system also can be utilized to completeshipping air bills and as a result, if the switches are activated,prevent the completion of an air bill, which effectively will prevent animproperly packaged shipment from being shipped.

In some embodiments, sensors 47, 50 may also be embedded in theinsulating materials 5, 7, such as gel packs. In these embodiments, thesensors provide information to the logistics system regarding thepresence, absence, and condition (e.g.—temperature) of the gel packs. Insome embodiments, the sensor/switch is an RFID tag, a temperaturesensor, or a magnet. FIGS. 1A and 1B show an example of an RFID tag 50or temperature sensor in one of the insulating materials.

FIG. 1C shows an embodiment of a packed insulating shipping container 1,where the gel packs 5 and 7, and the payload container 8, includemagnets or metallic materials 47, 48. In this embodiment, thesensors/switches 2, 4, 6 are magnetic switches. The magnetic switches 2,6 interact with the magnets 47 in the gel packs, while the magneticswitches 4 interact with the magnets 48 in the payload container. Whenproperly packed, this interaction indicates that the insulated shippingcontainer 1 is ready for shipping and this information is preferablyreceived by the logistics system. If the magnets or metallic materials47, 48 are not properly lined up with the magnetic switches 2, 4, 6 inthe insulated shipping container 1, the insulated shipping container hasnot been properly packed and this information is preferably received bythe logistics system.

The tracking system receives the type of shipping container used to shipthe biologic. The tracking system receives data from the sensors withinthe insulated shipping container. The tracking system determines whetherthe shipping container was properly packed based on the information fromthe sensors. If the shipping container was not properly packed, then thetracking system prevents a shipping bill from being completed and maysend a message to a designated user. If the shipping container wasproperly packed, the computer releases the insulated shipping containerfor shipping to its destination.

Proper packing of the shipping container occurs when a bottom insulatingmaterial (such as an ice pack or a gel pack) is accurately placed in theinsulated shipping container, the payload container is next accuratelyplaced in the shipping container, and the top insulating material (suchas an ice pack or a gel pack) is accurately placed on top of the payloadcontainer.

The tracking/logistics system is accessed and the shipping container isselected from a list of shipping containers. The system verifies whetherthe bottom insulating material, the payload container and the topinsulating material are properly placed based on the informationreceived from the sensors/switches in the shipping container. Thetracking/logistics system also preferably verifies whether theinsulation materials or gel packs are within an acceptable startingtemperature range. If the system has verified that the materials havebeen packed correctly and, in embodiments with a temperature sensor, arewithin an acceptable starting temperature range, the tracking systemwill permit proceeding to the next step in the shipping process. If thetracking system reports that the packing procedure has not beenperformed correctly, the user is not permitted to continue with theshipping process. The operator must inspect the shipping container toensure that it is packed out correctly with the required components.

In preferred embodiments, once the package is approved for shipping, theuser enters the time the shipping container was loaded (the “pack outtime”) and the stability period for the biologic (or “payload”) in thepayload container into the tracking/logistics system. The user mayconfigure specific alert messages to various recipients regarding theshipment location, arrival at destination, and time remaining in astability countdown timer. The computer receives the pack out time andthe stability period, and begins to countdown the stability period onceit receives that information. The computer may also send alertsregarding the countdown timer and the stability period to one or moreusers.

The countdown timer is activated within the tracking system, which is incommunication with a shipping container. A stability countdown timer maybe displayed by the tracking/logistics system and is activated once thecomputer receives values for the pack out day and time and the stabilityperiod. Once activated, the countdown timer alerts the appropriateparties who have been entered as alert recipients in the trackingsystem. Periodic updated alerts may also be programmed and communicatedto recipients via e-mail messages and SMS.

The tracking system also may communicate location data, which may becommunicated by the long-range communications to the tracking system,along with the time left on the stability countdown timer. FIGS. 2Athrough 2E show examples of information in the logistics system. Thealerts provide real time locations (e.g. ˜5 miles from destination) andcan be acted upon based on those locations. Some examples for alerts areshown in FIG. 2C.

FIG. 2C shows an example of a pack-out time and stability period thathas been received by the computer. FIG. 2D shows stability countdowntimers for recently delivered shipments, with the stability timeremaining. The countdown timer continues to run once the shipment hasbeen delivered, to keep all users aware of the continued need to get thetime and/or temperature sensitive biologic material to the actualrecipient.

Many biologics have very short shelf lives, which makes it verydifficult to ship them around the world. Also, there are often delays inshipping, which would make a biologic no longer viable when it reachesits destination. The addition of a stability countdown timer permitsanyone interested in the amount of time the biologic has been intransport, to obtain the amount of time left for the biologic beingshipped to be viable. Therefore, this method is able to calculate howmuch time is left in the viability/stability period.

Once the computer receives the pack out time and stability period, thetime left in the stability period is calculated and the computer beginsthe countdown. By monitoring the stability time period, there is anincrease in the awareness regarding where the package is and how thataffects the stability and viability of the biologic being transported.

Throughout transport of the shipment, the alerts as to the location ofthe container, as well as the amount of time left on the countdowntimer, may be sent to the designated recipients. The information aboutwhen the container was delivered may also be preferably provided to thedesignated recipients. Since many medicines or other biologics need tobe used within a validated protocol time period, this information iscrucial in the decision making processes of clinicians and otherpractitioners once the biologic is received and for clinicaladministration purposes.

Information from the countdown timer may be sent to one or more users.The computer may display it in a preconfigured app, or the user may login to access the current status of the countdown timer. When thecountdown timer is reviewed, the computer displays to the user theamount of time left, and where the container is. If there is a delayduring transit that would adversely affect the biologic, the user canutilize this information to determine whether the biologic could stillbe transported in an alternative manner while maintaining stability,aiding in making decisions about alternative transport.

In a first step of monitoring a stability countdown timer of a shipment,the pack out time is received by a tracking system. The shelflife/stability period of the particular biologic being shipped is alsopreferably received by the system. During transit of the shipment, thetracking system may provide users access to the time remaining in thestability period. The tracking system may send alerts regarding the timeremaining on the stability countdown timer. These alerts may be sent viae-mail, SMS, MMS, or other methods. By monitoring the stability periodof a biologic during transport, the delivery and administration timeand/or temperature sensitive medicines to the patient or laboratory canbe closely monitored and evaluated.

FIGS. 3A and 3B shows examples of payload containers 8 in embodiments ofthe present invention. A payload container 8, containing the biologicpayload (e.g. biologic-based medicine), is designed to fit specificallyin place within an insulated shipping container. The payload container 8in FIG. 3A includes a top 35, which may be a clam shell or otheropening. The payload container 8 also includes a cavity 36 for insertionand storage of the biologic based material. In FIG. 3B, the cavity 36 islocated so that the primary payload container 43 (which contains thebiologic being transported) is inserted horizontally into the payloadcontainer 8. In other embodiments, the cavity 36 or storage volume isconfigured differently, for example, as a cavity formed by a bottom andsidewalls of the payload container 8. The cavity 36 is also preferablylined with packing material 42 (for example bubble wrap, dunnage, orcushion foam) to protect the payload from mechanical vibration, shock,or other forms of stress during transit.

As shown in FIGS. 3A and 3B, the payload container 8 preferably includesa communications device 9 which monitors a range of parameters ofconditions of the payload and transmits the information regarding theseconditions to a long-range communications device 3, which itself isembedded in the insulated shipping container (see FIGS. 1A through 1C).Some of these parameters include, but are not limited to, location,temperature, pressure, humidity, tilt, exposure to light, acceleration,battery life, and communication signal strength. For example, thepayload container 8 may include an RFID tag or other communicationsdevice to identify the location of the payload container 8. The payloadcontainer 8 may also contain a temperature sensor 10, such as athermocouple. The temperature sensor is connected to the communicationsdevice 9, preferably either by direct wiring or wireless communication.

The communication device 9 may transmit information to other devicesutilizing near field communication methods. In some embodiments, thepayload communications device 9 is a near field or close proximityelectronic communication device that provides location and temperatureinformation and may communicate using Bluetooth®, Wi-Fi or other formsof near field communication (NFC). Some near field or close proximityelectronic communications devices 9 that could be used include, but arenot limited to, active RFID devices, RFID tags, RF transmitters,iBeacon™ transmitters, ZigBee® transmitters, Bluetooth transmitters,Wi-Fi radios, and other wireless transmitters.

When the insulated shipping container reaches its destination, thepayload container 8 is often unpacked and separated from the insulatedshipping container 1. At that point, prior art methods of tracking aninsulated shipping container fail, since the payload container 8 is nolonger associated with the shipping container. But, the payloadcontainer 8 still needs to be monitored, since the temperature of thepayload container 8 may increase to a temperature point above viabletemperatures for the biologic. In addition, the payload container 8would likely need to arrive at a specific location in a certain timeperiod.

A payload container 8 that includes an internal communications device 9allows for the tracking of the payload container 8 itself, after itreaches its general destination (such as the dock of a hospital). Atemperature sensor 10, such as a thermocouple, may also be included inthe payload container 8, to continue to monitor the temperature of thepayload container 8 even after it has been removed from the insulatedshipping container 1. The communications device 9 can communicate with anetwork, allowing communication to take place between the payloadcontainer 8 and a network associated with the destination. For example,the communications device 9 may communicate with a mobile device, whichcommunicates wirelessly with a hospital network. The payload container 8of the present invention provides autonomy of the payload container 8within the facility, preferably for at least an hour or two.

Rather than losing the ability to track the payload container 8 when itreaches the dock or another location where it is unpacked from theinsulated shipping container, the payload container 8 may be trackeduntil it gets to the patient. The payload container 8 preferablyincludes electronics 9 that transmit location and, in preferredembodiments, also temperature 10. Since the payload container 8 stilltransmits information after it is unpacked, information is stillreceived up until the biologic has reached the patient's bedside or thedoctor attending to the patient.

While the payload container 8 is shown as specific shapes in thefigures, any payload container capable of safely housing the biologic ofinterest may be used.

A logistics system preferably acts as a hub for the information flowbetween the insulated container, the payload container and the users whomay be involved in the shipping, receiving and use of the materialswhich are being shipped. These users include, but are not limited to,clinicians and patients. The logistics system preferably includes acommunications network having the ability to prevent the completion ofan air bill for the shipment of a temperature sensitive shipment in thecase that the shipment pack out has not been performed properly.

FIG. 4A shows a shipping or storage container 40 with a communicationsdevice 3 and a cavity 12 for receiving a payload container 8. FIG. 4Bshows the insulated shipping or storage container of FIG. 4A, packedwith insulating materials 5, 7, and a payload container 8 without itsown separate shielding. The insulated shipping container 40 includes abottom or body 20 and a top or lid 15. The body 20 includes a base 23and sidewalls 13 that extend up from the base 23. The body 20 defines anopen storage volume or cavity 12. The top 15 is removable to provideaccess to the storage volume 12. When the top 15 is placed on the body20, the storage volume 12 is closed. The top 15, the base 23 and thesidewalls 13 preferably include multiple layers of insulating materials.

The communications device 3 is preferably housed in a cavity 26 in thebase 23 of the insulated shipping container 40. In preferredembodiments, the communications device 3 is a long-range communicationsdevice that uses near field electronic communication to provideinformation and may communicate using Bluetooth®, Wi-Fi or other formsof near field communication (NFC). In some embodiments, thecommunications device 3 includes GPS, a cellular modem, and/or otherwireless communication devices. The communication device 3 may transmitinformation to other devices utilizing near field communication methods.Some examples of these communications devices include, but are notlimited to, cellular communication devices (e.g.—cellular phones,cellular modems, code division multiple access systems, global systemfor mobile communications, and other cellular portions of the spectrum),RF transmitters, active RFID devices, RFID tags, iBeacon™ transmitters,ZigBee® transmitters, Bluetooth® transmitters, Wi-Fi radios, otherwireless transmitters, or other near field communication signals ordevices. In some embodiments, the materials attenuate ionizing radiation(e.g.—X-ray radiation such as airport screening devices).

The wireless communication devices are preferably permanently integratedinto the base 23 of the container 40. The container 40 also includesshielding 60 on the interior of the cavity 26 and shielding 61 on theunderside of the lid 15 of the container 40. The shielding 60 and 61 maybe located anywhere between the communications device 3 and the payloadcontainer 8. For example, while the shielding 60 is shown on all of thesidewalls in FIG. 4A, the shielding may only be located in a positionbetween the communications device 3 and the payload container 8 receivedwithin the cavity 12. In some of these embodiments, the shielding 60 isa plate located between the communications device 3 and the payloadcontainer 8. If plates are used, they are placed so that they stillpermit the cellular modem, or other communications device, to transmit.In other embodiments, a plate may be placed within the cavity 26 in alocation that shields the payload container 8 from the communicationsdevice 3, but still permits transmission of the communications device 3to a remote location.

The shielding 60, 61 may be made of any shielding material that is ableto block the radiation emitting from the communications device,including, but not limited to, lead, aluminum, bronze, copper, nickel,zinc, another metal, conductive plastics, or carbon based materials. Theform of the shielding 60, 61 is preferably selected from the groupconsisting of plates, coatings, inserts, sprayed on liners, mesh, foil,foam, paints, inks, solid plates or pieces, or a film adhesive. Thesprayed on liner may be made of electric arc sprayed on zinc. If platesare used, they are preferably made from lead or another metal, and theyare placed so that they still permit the communications device, totransmit. If coatings are used, the coatings chosen are preferably madeof materials that allow X-rays to pass through so that all interiorspaces of the shipping container are still visible. Any combinations ofmaterials and types of shielding may be used.

The insulated shipping container 40 also preferably includes a powercompartment 45, which provides power to the electronics in the insulatedshipping container 40. In some preferred embodiments, the powercompartment 45 is a battery compartment, which contains a battery pack.The battery pack preferably powers the communications device 3. Whilethe power compartment 45 is shown on the bottom of the base 23 of theinsulated shipping container 40 in the Figures, the power compartment 45may be in alternative locations, and is preferably connected (via wiringor wirelessly) to the communications device 3.

The communications device 3 permits the insulated shipping container tocommunicate to an outside source, including, but not limited to, acloud-based database or program, device computers, server computers, orother devices. It should be noted that the term “outside” means with adevice other than present within the shipping or storage container.While the communications device 3 is shown placed in the base 23 of theshipping container 40 in FIG. 4A, the communications device may be inany location where it does not interfere with other components of thecontainer.

This communication device 3 communicates to an outside source including,but not limited to, a cloud-based database or program, device computers,server computers, or other devices. The outside source can alsodetermine whether certain parameters are not within appropriate rangesand notify users.

FIG. 4C shows the insulated shipping or storage container 40 of FIG. 4A,packed with insulating materials and a shielded payload container 80.The shielding 81 may form the exterior of the payload container 80, ormay line one or more of the interior walls of the payload container 80.In preferred embodiments, the shielding 81 is located along the entireperimeter of the payload container 80. However, the shielding 81 mayalternatively only be located on some of the walls, preferably thosethat are located between the communications device 3 and the payloadcontainer 80 when the payload container 80 is packed in the shippingcontainer 40. The shielded payload container 80 could alternatively beused in an insulated shipping container 40 without its own shielding.

The shielding 81 in the payload container 80 may be made of anyshielding material that is able to block the radiation emitting from thecommunications device, including, but not limited to, lead, aluminum,bronze, copper, nickel, zinc, another metal, conductive plastics, orcarbon based materials. The form of the shielding is preferably selectedfrom the group consisting of plates, coatings, inserts, sprayed onliners, mesh, foil, foam, paints, inks, solid plates or pieces, or afilm adhesive. The sprayed on liner may be made of electric arc sprayedon zinc. If plates are used, they are preferably made from lead oranother metal and are placed so that they still permit thecommunications device, to transmit, if one is present in the payloadcontainer. If coatings are used, the coatings chosen are preferably madeof materials that allow X-rays to pass through so that all interiorspaces of the shipping container are still visible. While the shieldingis shown within the container 40 of FIG. 4A, both the shielding and thesensors for detecting radiation exposure (see FIGS. 6-7 below) could beused in combination with any of the other embodiments described herein.

FIG. 5 shows an insulated shipping or storage container 100 with acommunications device 3 (e.g.—a cellular modem or other near fieldcommunications device) plus at least one non-ionizing radiation sensor51 to detect RF energy or other near field radiation exposure. Thenon-ionizing radiation sensor 51 may be a radiation detector. Oneexample of a radiation detector is a modular device with a wired sensorincorporating a radiation detector diode (such as the SPD9441 RadiationDetector PIN Diode, Solid State Devices, Inc., La Mirada, Calif.).Another example is a USB spectrum analyzer for detecting and measuringemitted electromagnetic radiation from cell phones or other sources(such as the TSA6G1 USB Mini Spectrum Analyzer, Triarchy TechnologiesCorp., Surrey, British Columbia). In preferred embodiments, thecommunications device 3 is a long-range communications device that usesnear field electronic communication to provide information and maycommunicate using Bluetooth®, Wi-Fi or other forms of near fieldcommunication (NFC). In some embodiments, the communications device 3includes GPS, a cellular modem, and/or other wireless communicationdevices. The communication device 3 may transmit information to otherdevices utilizing near field communication methods. Some examples ofthese communications devices include, but are not limited to, cellularcommunication devices (e.g.—cellular phones, cellular modems, codedivision multiple access systems, global system for mobilecommunications, and other cellular portions of the spectrum), RFtransmitters, active RFID devices, RFID tags, iBeacon™ transmitters,ZigBee® transmitters, Bluetooth® transmitters, Wi-Fi radios, otherwireless transmitters, or other near field communication signals ordevices. In some embodiments, the materials attenuate ionizing radiation(e.g.—X-ray radiation such as airport screening devices).

While two sensors 51 are shown in the figure, one sensor or more thantwo sensors could alternatively be used. The sensors 51 are preferablyat least partially embedded or fully embedded into one or more of thewalls of an insulated shipping or storage container. In one embodiment,the container 100 also preferably includes wiring 55 to connect thesensors 51 to the communications device 3. In other embodiments, thesensors 51 are wireless. In both wired and wireless embodiments, thesensors 51 preferably communicate with the communications device 3 topreferably get the data transmitted to the cloud or another wirelesslocation. The insulated shipping container 100 is packed with insulatingmaterials 5, 7 and the payload container 8. The insulated shippingcontainer 100 could also contain shielding (as shown in FIGS. 4A to 4C)to shield the payload container 8 from the communications device 3.

FIG. 6 shows an insulated shipping container 110 with a communicationsdevice 3 (e.g.—a cellular modem or other near field communicationsdevice) plus at least one sensor 52 to detect ionizing radiation, suchas X-ray exposure. The ionizing radiation sensor 52 may be a radiationdetector. One example of a radiation detector is a modular device with awired sensor incorporating a radiation detector diode (such as theSPD9441 Radiation Detector PIN Diode, Solid State Devices, Inc., LaMirada, Calif.). Another example is a USB spectrum analyzer fordetecting and measuring emitted electromagnetic radiation from cellphones or other sources (such as the TSA6G1 USB Mini Spectrum Analyzer,Triarchy Technologies Corp., Surrey, British Columbia). In preferredembodiments, the communications device 3 is a long-range communicationsdevice that uses near field electronic communication to provideinformation and may communicate using Bluetooth®, Wi-Fi or other formsof near field communication (NFC). In some embodiments, thecommunications device 3 includes GPS, a cellular modem, and/or otherwireless communication devices. The communication device 3 may transmitinformation to other devices utilizing near field communication methods.Some examples of these communications devices include, but are notlimited to, cellular communication devices (e.g.—cellular phones,cellular modems, code division multiple access systems, global systemfor mobile communications, and other cellular portions of the spectrum),RF transmitters, active RFID devices, RFID tags, iBeacon™ transmitters,ZigBee® transmitters, Bluetooth® transmitters, Wi-Fi radios, otherwireless transmitters, or other near field communication signals ordevices. In some embodiments, the materials attenuate ionizing radiation(e.g.—X-ray radiation such as airport screening devices).

While two sensors 52 are shown in the figure, one sensor or more thantwo sensors 52 could alternatively be used. Although a communicationsdevice 3 is shown in this figure, simple shipping containers withoutthese devices could also utilize the radiation sensors 52 shown in thisfigure. The sensors 52 are preferably at least partially embedded orfully embedded into one or more of the walls of an insulated shippingcontainer. In one embodiment, the container also preferably includeswiring 55 to connect the sensors 52 to the communications device 3. Inother embodiments, the sensors 52 are wireless. In both wired andwireless embodiments, the sensors 52 preferably communicate with thecommunications device 3 to preferably get the data transmitted to thecloud or another wireless location. The insulated shipping container 110is packed with insulating materials 5, 7 and the payload container 8.The insulated shipping container 110 could also contain shielding (asshown in FIGS. 4A to 4C) to shield the payload container 8 from thecommunications device 3 if that shielding did not interfere with X-rayequipment necessary to scan the biologic being shipped.

The dosimeters/sensors 52 are connected to the electronics of theinsulated shipping container 110 (either through wiring or wirelessly)and the sensors 52 protrude into the payload cavity 12 in FIG. 6. Inother embodiments (not shown), since the X-rays pass through the entirecontainer during a TSA or other scan, the sensors 52 could be built intothe electronics of the container or are located elsewhere in thecontainer 110. For example, the dosimeter/sensor 52 could have separateelectronics or may have electronics which are part of the communicationsdevice or other existing monitoring electronics in an insulated shippingcontainer.

Insulated shipping containers could alternatively utilize bothnon-ionizing radiation sensors 51 and ionizing radiation sensors 52, tosense exposure of multiple types of radiation.

FIG. 7 shows a payload container 90 with shielding 91 and non-ionizingradiation sensors 53 and ionizing radiation sensors 54. Radiationsensors 53 preferably sense exposure to near field radiation, such as RFenergy, and radiation sensors 54 preferably sense exposure to X-rayradiation. In some embodiments, the payload container 90 also preferablyincludes wiring 94 to connect the sensors 53 to the communicationsdevice 92 and wiring 95 to connect the sensors 54 to the communicationsdevice 92. In other embodiments, the sensors 53 and/or 54 are wireless.In both wired and wireless embodiments, the sensors 53, 54 preferablycommunicate with the communications device 92 to preferably get the datatransmitted to the cloud or another wireless location.

In preferred embodiments, the communications device 92 uses near fieldelectronic communication to provide information and may communicateusing Bluetooth®, Wi-Fi or other forms of near field communication(NFC). In some embodiments, the communications device 92 includes GPS, acellular modem, and/or other wireless communication devices. Thecommunication device 92 may transmit information to other devicesutilizing near field communication methods. Some examples of thesecommunications devices include, but are not limited to, cellularcommunication devices (e.g.—cellular phones, cellular modems, codedivision multiple access systems, global system for mobilecommunications, and other cellular portions of the spectrum), RFtransmitters, active RFID devices, RFID tags, iBeacon™ transmitters,ZigBee® transmitters, Bluetooth® transmitters, Wi-Fi radios, otherwireless transmitters, or other near field communication signals ordevices. In some embodiments, the materials attenuate ionizing radiation(e.g.—X-ray radiation such as airport screening devices).

The shielding 91 may form the exterior of the payload container 90, ormay line one or more of the interior walls of the payload container 90.In preferred embodiments, the shielding 91 is located along the entireperimeter of the payload container 90. However, the shielding 91 mayalternatively only be located on some of the walls, preferably thosethat would be located between the communications device 3 of theinsulated shipping or storage container and the payload container 90when the payload container 90 is packed in the shipping container. Inother embodiments (not shown), the shielding surrounds a communicationsdevice 92 and/or a power compartment 93 within the payload container 90or is located between the communications device 92 and the payload inthe payload container 90. For example a shielding plate could be placedbetween the communications device 92 and the payload in the payloadcontainer 90. The plate is placed so that it still permits the cellularmodem or other communications device, to transmit. The shielded payloadcontainer 90 could be used in an insulated shipping container 40 withits own shielding (see FIG. 4A).

The shielding 91 in the payload container 90 may be made of anyshielding material that is able to block the radiation emitting from thecommunications device, including, but not limited to, lead, aluminum,bronze, copper, nickel, zinc, another metal, conductive plastics, orcarbon based materials. The form of the shielding is preferably selectedfrom the group consisting of plates, coatings, inserts, sprayed onliners, mesh, foil, foam, paints, inks, solid plates or pieces, or afilm adhesive. The sprayed on liner may be made of electric arc sprayedon zinc. If plates are used, they are preferably made from lead oranother metal and are placed so that they still permit the cellularmodem or other communications device, if present in the payloadcontainer, to transmit. If coatings are used, the coatings chosen arepreferably made of materials that allow X-rays to pass through so thatall interior spaces of the shipping container are still visible. Whilethe shielding is shown with the container of FIG. 1A, both the shieldingand the sensors for detecting radiation exposure (see FIGS. 6-7 below)could be used in combination with any of the other embodiments describedherein.

While shielding 91 and sensors 53, 54 which detect multiple types ofradiation (RF energy sensors 53 and X-ray sensors 54) are all shown inthis figure, the payload container 90 may include only one of thesecomponents, or any combination of these components. In addition, asdiscussed above, the shielding 91 of the payload container 90 could belocated on the exterior or in the interior of the payload container 90.

For example, in some embodiments, the payload container includes thesensors 53, 54, but no shielding. In some of these embodiments, thepayload container does not have a communications device or powercompartment, the sensors 53, 54 are wireless, and communicate with thecommunication device in an insulated shipping container that hasshielding. That communications device is able to store and transmit theexposure data to the cloud.

In other embodiments, the payload container includes only sensors 54, tosense the X-ray exposure of biologics being subject to TSA scans. Insome of these embodiments, the payload container does not include anycommunications devices or a power compartment, and the X-ray sensors arewireless and communicate with the communications device in an insulatedshipping container that has shielding. That communications device isable to store and transmit the exposure data to the cloud.

Although the payload container 90 is shown as a particular shape in FIG.7, any shaped payload container 90 could include sensors 53, sensors 54,and or shielding 91. The payload container 90 shown in FIG. 7, or anyvariation of the payload container 90, could be used in any of theembodiments described herein.

The shielding and radiation exposure sensors described in FIGS. 4through 7 could be used in combination with any of the other shippingcontainer and logistics embodiments described in this application. Forexample, FIG. 8 shows a shipping container 120 in an embodiment of thepresent invention, with the shielding 60, 61, shown in FIG. 4 and theswitches and/or sensors 2, 4, 6 shown in FIG. 1.

The embodiments described herein, particularly the shielding andmonitoring embodiments described with respect to FIGS. 4-8 (but also theother embodiments described herein) could be used in combination withany insulated shipping container available. For example, the devices inUS Patent Publication 2014/0138392, entitled “Contents Rack for Use inInsulated Storage Containers”, published May 22, 2014, hereinincorporated by reference, could use the shielding and monitoringembodiments as described herein.

All of the patent and nonpatent references discussed herein areincorporated herein by reference.

Accordingly, it is to be understood that the embodiments of theinvention herein described are merely illustrative of the application ofthe principles of the invention. Reference herein to details of theillustrated embodiments is not intended to limit the scope of theclaims, which themselves recite those features regarded as essential tothe invention.

What is claimed is:
 1. An insulated shipping container comprising: aninsulated shipping container body comprising a base and sidewallsextending from the bottom of the base; a removable top which fits ontothe body; a plurality of sensors and/or switches at least partiallyembedded into the sidewalls of the insulated shipping body, wherein theplurality of sensors and/or switches are located in the body such thatthe sensors and/or switches sense a location of insulation material anda payload container placed into the insulated shipping container priorto shipping; and a long-range communications device located within acavity of the insulated shipping container body, to transmit informationfrom the sensors and/or switches to a communications network, whereinthe sensors and/or switches are operatively connected to the long-rangecommunications device, the plurality of sensors and/or switchesincluding a first pair of sensors and/or switches at least partiallyembedded on opposite walls of the insulated shipping container body thatsense a presence or absence of a first insulation material, a secondpair of sensors and/or switches at least partially embedded on oppositewalls of the shipping container that sense a presence or absence of asecond insulation material, and a third pair of sensors and/or switchesat least partially embedded on opposite walls of the shipping containerthat sense a presence or absence of the payload container between thefirst insulation material and the second insulation material.
 2. Theinsulated shipping container of claim 1, wherein the sensors and/orswitches of the plurality of sensors and/or switches are connected tothe long-range communications device by wiring.
 3. The insulatedshipping container of claim 1, wherein the sensors and/or switches ofthe plurality of sensors and/or switches are wirelessly connected to thelong range communications device.
 4. The insulated shipping container ofclaim 1, wherein the sensors and/or switches of the plurality of sensorsand/or switches are selected from the group consisting of: a) opticalsensors and/or switches; b) mechanical sensors and/or switches; c)magnetic switches; and d) any combination of a) through c).
 5. Theinsulated shipping container of claim 1, further comprising at least onetemperature sensor to measure a temperature of the insulation materialplaced in the insulated shipping container.
 6. A method of determiningwhether an insulated shipping container containing a temperaturesensitive biologic has been packed correctly, comprising the steps of: acomputer receiving sensor information from a plurality of sensors and/orswitches; and determining whether components in the insulated shippingcontainer have been packed correctly based on the sensor information,the insulated shipping container having: an insulated shipping containerbody, the insulated shipping container body having a bottom andsidewalls extending from the bottom of the body; and a top that fitsonto the body and is removable from the insulated shipping container,the plurality of sensors and/or switches, the plurality of sensorsand/or switches at least partially embedded into the sidewalls of theinsulated shipping body, the plurality of sensors and/or switcheslocated in the body such that the sensors and/or switches sense alocation of insulation material and a payload container placed into theinsulated shipping container prior to shipping, the plurality of sensorsand/or switches including a first pair of sensors and/or switches atleast partially embedded on opposite walls of the insulated shippingcontainer body that sense a presence or absence of a first insulationmaterial, a second pair of sensors and/or switches at least partiallyembedded on opposite walls of the shipping container that sense apresence or absence of a second insulation material, and a third pair ofsensors and/or switches at least partially embedded on opposite walls ofthe shipping container that sense a presence or absence of the payloadcontainer between the first insulation material and the secondinsulation material; and a long-range communications device locatedwithin a cavity of the insulated shipping container body, to transmitinformation from the sensors and/or switches to a communicationsnetwork, wherein the sensors and/or switches are operatively connectedto the long-range communications device.
 7. The method of claim 6,further comprising, if the shipping container was packed correctly, thecomputer authorizing shipping of the shipping container to adestination.
 8. The method of claim 6, further comprising, if theshipping container was not packed correctly, the computer sending anotification to a user to repack the shipping container.
 9. The methodof claim 6, further comprising the computer receiving informationregarding a temperature in the insulated shipping container.
 10. Themethod of claim 9, further comprising, if the shipping container waspacked correctly and the temperature in the insulated shipping containeris in an acceptable range, the computer authorizing shipping of theshipping container to a destination.
 11. The method of claim 9, furthercomprising, if the shipping container was not packed correctly or thetemperature in the insulated shipping container is not in an acceptablerange, the computer sending a notification to a user to repack theshipping container.
 12. The method of claim 6, wherein the sensorsand/or switches of the plurality of sensors and/or switches are selectedfrom the group consisting of: a) optical sensors and/or switches; b)mechanical sensors and/or switches; c) magnetic switches; and d) anycombination of a) through c).
 13. The method of claim 6, wherein theinsulated shipping container further comprises at least one temperaturesensor to measure a temperature of the insulation material placed in theinsulated shipping container.
 14. The method of claim 6, wherein thesensors and/or switches are connected to the long-range communicationsdevice by wiring.
 15. The method of claim 6, wherein the sensors and/orswitches are wirelessly connected to the long-range communicationsdevice.